Extension to the SCF2H , SCH2F , and SCF2R Motifs (R = PO (OEt )2, CO2R , Rf )

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Extension to the SCF2H , SCH2F , and SCF2R Motifs (R = PO (OEt )2, CO2R , Rf )

Tatiana Besset, Thomas Poisson

To cite this version:

Tatiana Besset, Thomas Poisson. Extension to the SCF2H , SCH2F , and SCF2R Motifs (R = PO

(OEt )2, CO2R , Rf ). Emerging Fluorinated Motifs : Synthesis, Properties, and Applications, Wiley-

VCH, pp.449-475, 2020, 978-3-527-82434-2 (oBook). - 978-3-527-82432-8 (ePDF). - 978-3-527-82433-5

(ePub). �10.1002/9783527824342.ch16�. �hal-02885856�

3.6. Extension to the SCF 2 H, SCH 2 F, and SCF 2 R motifs (R = PO(OEt) 2 , CO 2 R, Rf)

Tatiana Besset

* and Thomas Poisson

*

a

Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France.

b

Institut Universitaire de France, 1 rue Descartes, 75231 Paris, France.

tatiana.besset@insa-rouen.fr ; thomas.poisson@insa-rouen.fr

3.6.1 Introduction

Nowadays, organofluorine chemistry can be considered as a strategic research area in organic chemistry. Indeed, the importance of fluorinated molecules for the discovery of biologically active molecules cannot be denied in view of the marketed fluorine-containing drugs [1]. All refs must be under brackets before the punctuation. Apply all along the text. Therefore, to broaden the portfolio of available fluorinated groups, the community devoted lot of efforts.

As part of them, sulfur-containing fluorinated motifs are of high interest and already found applications in agrochemistry, for instance (eg. Fipronil and Toltrazuril). As the most popular sulfur-containing fluorinated group, the SCF

attracted lot of attention and plethora of methodologies were developed over the last decades [2]. Complementary, the quest for other sulfur-containing fluorinated groups is important, as their introduction can afford new and interesting physicochemical properties, as well as promising biological activities. In that purpose, considerable efforts were dedicated over the last ten years. As a result, the community has seen the development of practical methodologies to build up molecules having SCF

H, SCH

F and SCF

Rf motifs. In addition, recent efforts culminated in the development of new motifs bearing a functional group that can either be modulated or directly used in drug discovery program. As examples, one can mention the SCF

CO

R, SCF

PO(OEt)

and SCF

SO

Ph [3] groups.

In this chapter, the recent and most significant progress made for the access to SCF

H, SCH

F, SCF

PO(OEt)

SCF

COR, and SRf will be highlighted.

3.6.2 The SCF

H Motif

Over the last years, a strong interest was paid to the SCF

H group. Indeed, due to its unique

properties such as a its lipophilicity, its H-bonding ability [4] and due to the presence of a more

acidic proton compared with the one in the CF

H group, the development of new approaches

for its introduction onto various classes of compounds was reported. Two main strategies

were depicted, namely 1) the difluoromethylation of sulfur-containing molecules and 2) the

direct C-SCF

H bond construction. In this section will be reported the most relevant advances

made since 2016 [5].

3.6.2.1 Construction of the SCF

H Moiety

Due to the importance of the SCF

H group, various strategies were elaborated to build up a S- CF

H bond. Until 2016, the use of difluorocarbene precursors was the main approach.

Alternatives based on electrophilic and nucleophilic reagents or CF

H radical precursors were promising, although still in their infancy. A summary of the main reagents used in these transformations is depicted in the Scheme 3.6-1 [ 5 ].

Scheme 3.6-1 State of the art: reagents used for the difluoromethylation of sulfur-containing molecules until 2016.

In this section, will be described the recent advances made since 2016 to construct a S-CF

H bond.

In 2017, the group of Fu developed a methodology for the difluoromethylation of thiophenols under visible light photocatalysis [6]. Using the readily available difluorobromoacetic acid as a difluorocarbene precursor and an iridium complex as photocatalyst, a panel of thiophenols bearing halogens, ester, nitro as functional groups was functionalized in moderate to high yields (Scheme 3.6-2a). Note that even the difluoromethylation of 2-pyridinethiol was smoothly achieved (Scheme 3.6-2b).

Scheme 3.6-2 Difluoromethylation of thiophenols under visible light photocatalysis.

Another difluorocarbene precursor, namely the diethyl bromodifluoromethylphosphonate, was also used in combination with thiourea as the sulfur source [7]. With this system, Yi and coworkers successfully functionalized in a one-pot three-step sequence, a panel of heteroaromatic compounds (indoles, pyrroles) and electron-rich arenes (Scheme 3.6-3).

Scheme 3.6-3 Difluoromethylation of heteroaromatic compounds and electron-rich arenes using diethyl bromodifluoromethylphosphonate and thiourea.

In 2017, the groups of Qing and Studer independently developed a method for the difluoromethylation of thiols using a difluoromethyltriphenylphosphonium salt, via a radical process. Indeed, Qing and co-workers reported a Ir-catalyzed difluoromethylation reaction under visible light irradiation [8]. A panel of (hetero)aryl- and alkyl-thiols was functionalized (Scheme 3.6-4a). In the case of Studer’s group, a transition metal free process was developed and not only (hetero)arylthiols, benzylic ones but also a benzeneselenol were difluoromethylated, leading to the corresponding products in moderate to high yields (Scheme 3.6-4b) [9].

1) I₂ (1 equiv), KI (1 equiv) thiourea (2 equiv) 1,4-dioxane/H₂O, rt 2) NaOH 5M, 50 °C 3) BrCF₂PO(OEt)₂ (1 equiv), rt

95%

and 27 examples, 32-95%

NH

SCF₂H NH

Selected examples:

N H Cl

SCF₂H

63%

MeO OMe

NH₂ SCF₂H

47%

N H H₂N

SCF₂H

80%

Scheme 3.6-4 Difluoromethylation of thiol derivatives with a difluoromethyltriphenylphosphonium salt.

An alternative was suggested by the group of Yi for the difluoromethylation of thiols (Scheme 3.6-5) [10]. Aiming at developing a general method for the construction of S-Rf bond (Rf = CF

, CF

H, C

F

), the authors reported a silver catalyzed difluoromethylation of various (hetero)aromatic thiols using sodium difluoromethanesulfinate (HCF

SO

Na).

Scheme 3.6-5 A silver-catalyzed difluoromethylation of thiol derivatives.

HCF₂SO₂Na (2 equiv) AgNO₃ (10 mol%)

K₂S₂O₈ (2 equiv)

CH₃CN/H₂O, 80 °C 51%

and 6 examples, 61-89%

MeO SH MeO SCF₂H

same as above

same as above

S N

SCF₂H 61%

78%

N N

SCF₂H S

N SH

N N

SH

3.6.1.2 Direct formation of a C–SCF

H bond

Major advances were made for the direct construction of a C-SCF

H bond, as demonstrated by the contributions from several research groups. Novel methods and original reagents (nucleophilic and electrophilic ones) were developed to construct C-SCF

H bonds [ 5 ], as summarized in Scheme 3.6-6.

Scheme 3.6-6 State of the art: available tools for the direct difluoromethylthiolation until 2016

Since then, further developments were realized for the difluoromethylthiolation reaction using nucleophilic reagents, newly designed electrophilic sources and by means of radical precursors.

3.6.2.2.1 Difluoromethylthiolation Reaction by a Nucleophilic Pathway

A pioneer work was reported by the group of Goossen. They developed the in situ generation

of a nucleophilic CuCF

H reagent from TMSCF

H, an activator (CsF or Cs

CO

) and a suitable

copper salt. This reagent was used for the functionalization of organothiocyanate derivatives,

themselves prepared from various classes of precursors (alkyl bromides and mesylates, aryl

diazonium salts and electron rich arenes)[11]. As another milestone, the first nucleophilic

difluoromethylthiolation reagent ([(SIPr)Ag(SCF

H)], 1), developed by Shen and co-workers,

was applied as a nucleophilic SCF

H source in a copper-mediated difluoromethylthiolation of

aryl diazonium salts and for the Pd-catalyzed functionalization of (Het)ArX (X = I, Br and OTf)

[12]. In 2018, the same group showed that a slightly modified catalytic system allowed the

functionalization of aryl bromides, triflates and chloride as well as two examples of

(hetero)aryl chloride [13]. Indeed, in the presence of the [Pd-1] and BrettPhos, in a catalytic

fashion, the difluoromethylthiolation of various aromatic derivatives was achieved (46

examples, up to 98% yield). With this tool in hand, the functionalization of natural, medicinal

and material molecules was possible, demonstrating the potential of such approach for the

late-stage functionalization (Scheme 3.6-7).

Scheme 3.6-7 Pd-catalyzed difluoromethylthiolation of (Het)ArX (X = Br, OTf and Cl) with the nucleophilic SCF

H source 1.

3.6.2.2.1 Difluoromethylthiolation Reaction using Electrophilic Reagents

From the key contributions made by the group of Shen and Shibata in the design of electrophilic SCF

H sources, 2[14] and 3a-d (Scheme 3.6-6) [15], several advances were made using either these well-known electrophilic SCF

H sources or based on original approaches.

In 2018, Xie, Zhu and coworkers reported a transition metal free, umpollung difluoromethylthiolation of tertiary alkyl ethers using 2 [16]. Although restricted to only three examples, the selective difluoromethylthiolation of a C–O bond was successfully achieved using a synergistic organophotoredox catalysis and organocatalysis (Scheme 3.6- 8).

Scheme 3.6-8 Difluoromethylthiolation of tertiary alkyl ethers using 2.

Note that Shibata and co-workers recently used these two classes of reagents (2 and 3a-d) as SCF

H sources in the synthesis of racemic -SCF

H-containing--ketoallylesters. The latters were then converted into the corresponding enantioenriched ketones through a Pd-catalyzed asymmetric Tsuji decarboxylative allylic alkylation with up to 94% ee [17]. More recently, the same group developed a diastereoselective difluoromethylthiolation of indanone-based - ketoesters thanks to the use of the ylide 3d by means of a chiral auxiliary (Scheme 3.6-9) [18].

One acyclic enamino ester was also functionalized albeit in a poor 12% ee [19].

[Pd-1] (5-10 mol%) Brettphos (5-10 mol%)

1 (1.2 equiv) KBr (0-2 equiv)

THF, 50-80 °C 23-99%

46 examples R

X

R

SCF₂H

Pd NH₂ OMs

Brettphos

[Pd-1]

X = Br, OTf, Cl

a) Reaction with aryl bromide, triflate and chlorides:

b) Reaction with heteroaryl chlorides:

N Cl N SCF₂H

N Cl

N SCF₂H same

as above same as above

64%

51%

Scheme 3.6-9 Diastereoselective difluoromethylthiolation of indanone-based -keto esters using 3d.

Besides, the quest for new electrophilic SCF

H sources emerged over the last years and original sources were developed, especially starting from the HCF

SO

Cl, HCF

SO

Na and HCF

SOCl reagents.

In 2016, Zhao, Lu and coworkers reported the in situ generation of the electrophilic difluoromethylsulfenyl chloride (HCF

SCl) after reduction of the difluoromethanesulfonyl chloride (HCF

SO

Cl) by PPh

[20]. With this tool in hand, the difluoromethylthiolation of a panel of indoles was achieved, leading to the corresponding products in good to high yields.

Note that other heteroaromatic derivatives (pyrrole, indolizine, pyrazole derivatives…) and electron-rich arenes were functionalized under these reaction conditions. The presence of n- Bu

NI as an additive was mandatory, presumably for the generation of iodine in the course of the reaction, which might facilitate the transformation (Scheme 3.6-10).

1) 3d (2 equiv) CuBr (20 mol%)

Toluene, rt

2) 1M HCl 56%, 85% ee

and 7 examples, 32-63%

12-93% ee O

CO₂Me SCF₂H NH

CO₂Me Naphth

a) Reaction with indole derivatives:

N H O₂N

SCF₂H

N H O₂N

75%

and 18 examples, 37-96%

HCF₂SO₂Cl (1.2 equiv) PPh3 (2.4 equiv) n-Bu₄NI (0.2 equiv)

Toluene, 60 °C

b) Selected examples with other heteroarenes and electron-rich arenes:

same as above

same as above

N N OH

SCF₂H

Ph

N N OH

Ph

OMe

MeO OMe

OMe

MeO OMe

SCF₂H

46%

same

as above N

SCF2H EtO₂C

H N

EtO₂C

H

57%

63%

and 3 examples, 46-83%

Scheme 3.6-10 Difluoromethylthiolation of heteroaromatic derivatives and electron-rich arenes using PPh

as the reducing agent and HCF

SO

Cl.

The combination of HCF

SO

Cl and PPh

was then applied to the functionalization of other classes of compounds. Zhao, Lu and co-workers studied the difluoromethylthiolation of thiol derivatives using HCF

SO

Cl combined with PPh

in the presence of NaI as the iodine source (Scheme 3.6-11) [21].

Scheme 3.6-11 Difluoromethylthiolation of thiol derivatives using PPh

as the reducing agent and HCF

SO

Cl.

In the same vein, in 2018, Yi, Zhang and co-workers investigated the difunctionalization of unsaturated compounds. Indeed, using the difluoromethanesulfonyl chloride (HCF

SO

Cl) in the presence of PPh

, the chloro-difluoromethylthiolation of alkenes (styrene derivatives and other classes of alkenes) and terminal alkynes was achieved leading to the corresponding products in moderate to high yields with a high atom economy [22]. Note that when styrene derivatives were used, the Markovnikov products were regioselectively obtained, while the other alkenes provided the anti-Markovnikov adducts preferentially (Scheme 3.6-12).

Scheme 3.6-12 Chloro-difluoromethylthiolation of alkenes and alkynes using the HCF

SO

Cl /PPh

system.

In 2016, in the course of their investigations towards the development of a general methodology for the fluoroalkylthiolation of electron rich arenes and thiol derivatives using fluoroalkylsulfonyl chloride, the group of Yi depicted few examples of

HCF₂SO₂Cl (2 equiv) PPh₃ (3 equiv)

DMF, 90 °C

89%

and 11 examples, 58-89%

a) Reaction with alkene derivatives:

Cl

SCF₂H

b) Reaction with alkyne derivatives:

HCF₂SO₂Cl (2 equiv) PPh₃ (3 equiv)

DMF, 90 °C

62%

and 9 examples, 42-82%

Cl

SCF₂H

F F

difluoromethylthiolation of indole and pyrrole derivatives using HCF

SO

Cl and (EtO)

POH as the reducing agent (Scheme 3.6-13) [23].

Scheme 3.6-13 Difluoromethylthiolation of indole and pyrrole derivatives using (EtO)

POH as the reducing agent and HCF

SO

Cl.

In 2017, Shibata and co-workers depicted the astute combination of

HF

CSO

Na/Ph

PCl/TMSCl for the electrophilic difluoromethylthiolation of C(sp

) and C(sp

)

centers [24]. Indeed, with this mild, metal- and base-free system, a large panel of nucleophiles

was functionalized including a wide range of phenol and naphthol derivatives. In addition, the

scope of the transformation was broad and the difluoromethylthiolation of other heterocyclic

compounds (pyrroles, indoles, …), electron-rich arenes as well as enamines, ketones and -

ketoesters was efficiently carried out (Scheme 3.6-14).

Scheme 3.6-14 Electrophilic difluoromethylthiolation of C(sp

) and C(sp

) nucleophiles with the HF

CSO

Na/Ph

PCl/TMSCl system.

The same year, the group of Yi and Zhang reported an alternative approach. Indeed, in their case, the HCF

SO

Na was reduced with (EtO)

POH in the presence of TMSCl to generate in situ an electrophilic SCF

H source [25]. With this metal free process, various heterocycles such as indoles (26 examples), pyrroles (10 examples) and other heteroarenes (eg. 7-azaindole, imidazo[1,2-a]pyridine,…) were difluoromethylthiolated. In addition, electron-rich arenes were also suitable substrates (8 examples, Scheme 3.6-15).

Scheme 3.6-15 Electrophilic difluoromethylthiolation of C(sp

) nucleophiles with the HF

CSO

Na/(EtO)

POH/TMSCl system

Finally, in 2018, Yi, Zhang and co-workers demonstrated that trifluoromethanesulfinyl chloride and difluoromethanesulfinyl chloride reacted as CF

SCl and HCF

SCl precursors [26]. Indeed, without additional reductant, the HCF

SOCl was prone to react with several indoles and ketones such as indanone derivatives, 1-tetralone and 1-acenaphthenone (Scheme 3.6-16).

a) Reaction with indole derivatives:

b) Reaction with pyrroles and other heteroarenes:

82%

and 7 examples,47-82%

73%

and 10 examples, 45-89%

c) Reaction with electron rich arenes:

N H MeO₂C

SCF₂H

N H MeO₂C

80%

and 25 examples, 18-93%

HCF₂SO₂Na (2 equiv) (EtO)2POH (3 equiv)

TMSCl (2 equiv) Toluene, 85 °C

NH EtO₂C Ph

NH EtO₂C Ph

SCF₂H HCF₂SO₂Na (2 equiv)

(EtO)₂POH (3 equiv) TMSCl (2 equiv) Toluene, 85-100 °C

OMe

OMe MeO

OMe

OMe MeO

SCF₂H HCF₂SO₂Na (2 equiv)

(EtO)₂POH (3 equiv) TMSCl (2 equiv) Toluene, 100 °C

N N

H N N

H SCF₂H

N N

H

N N

H SCF₂H 87%

88%

HCF₂SO₂Na (2 equiv) (EtO)₂POH (3 equiv)

TMSCl (2 equiv) Toluene, 85-100 °C

HCF₂SO₂Na (2 equiv) (EtO)₂POH (3 equiv)

TMSCl (2 equiv) Toluene, 85-100 °C

Scheme 3.6-16 Difluoromethylthiolation of indole derivatives and ketones with HCF

SOCl. Note that in case of indoles the reaction was carried out in CH

CN, 90 °C.

3.6.2.2.3. PhSO

SCF

H (4) as an efficient reagent for the radical difluoromethylthiolation Recently a strong interest was paid to thiosulfonate derivatives (ArSO

SRf) as emerging reagents for the introduction of sulfur-containing fluorinated moieties and in particular the SCF

H residue [27]. Therefore, in the following section, the major breakthroughs that have been recently developed using the PhSO

SCF

H as a SCF

H source for the direct introduction of the SCF

H moiety onto molecules will be summarized.

In 2016, the group of Lu and Shen investigated the synthesis and the application of the S- (difluoromethyl)benzenesulfonothioate (4, PhSO

SCF

H) [28]. This latter was synthesized via a one-pot two-step sequence from benzyldifluoromethylsulfide (Scheme 3.6-17). It was then applied for the difluoromethylthiolation of different classes of compounds.

The silver catalyzed difluoromethylthiolation of both aryl and alkyl boronic acids was described (Scheme 3.6-17a). The reaction turned out to be functional group tolerant (halides, ester, ketone, nitro…). In addition, to further demonstrate the synthetic utility of the reagent, the functionalization of aliphatic carboxylic acids was investigated under silver catalysis. Under these reaction conditions, the decarboxylative difluoromethylthiolation of cyclic and acyclic carboxylic acids (primary, secondary and tertiary ones) was achieved (Scheme 3.6-17b). Finally, the 1,2-difunctionalization of terminal aliphatic alkenes was studied leading to the corresponding phenylsulfonyl-difluoromethylthio derivatives in the presence or not of the silver catalyst. Note that styrenes and ,-unsaturated esters were reluctant substrates (Scheme 3.6-17c).

HCF₂SOCl (3 equiv)

Toluene, 110 °C

80%

and 7 examples, 73-90%

b) Reaction with ketone derivatives:

O

Cl

O

Cl

SCF₂H a) Reaction with indole derivatives:

N Cl

H N

Cl

H

SCF₂H HCF₂SOCl (3 equiv)

CH₃CN, 90 °C

75%

and 5 examples, 73-85%

Scheme 3.6-17 Synthesis and application of the S-(difluoromethyl)benzenesulfonothioate 4. SDS:

Sodium dodecyl sulfate.

In 2019, the same group reported a Co(III)-catalyzed hydro-difluoromethylthiolation reaction of unactivated alkenes as a complementary approach (Scheme 3.6-18). With this method, the functionalization of terminal alkenes and 1,1-disubstituted alkenes was achieved providing the expected products with a good Markovnikov selectivity [29]. The reaction demonstrated a large functional group tolerance (halides, aldehyde, sulfonate, cyano….).

Scheme 3.6-18 Co-catalyzed hydro-difluoromethylthiolation of unactivated terminal alkenes.

The difluoromethylthiolation of aromatic derivatives was also studied by several research

groups. The group of Li demonstrated that the reagent 4 was efficiently used as SCF

H source

under visible light irradiation for the radical difluoromethylthiolation. Various

(hetero)aromatic compounds (such as indoles, pyrroles, azaindoles, pyrazoles, isoxazole,

chromones, thiophene) and electron-rich arenes were functionalized at innate positions via a

metal-free process at room temperature (Scheme 3.6-19a) [30]. In the same vein, Wang, Wang

and co-workers studied the functionalization of aryldiazonium salts with 4 under photocatalytic conditions (Scheme 3.6-19b) [31].

Scheme 3.6-19 Photocatalyzed difluoromethylthiolation of (Het)ArH and (Het)ArN

BF

derivatives with 4.

In 2018, the synthesis of difluoromethylthioester derivatives with the aid of reagent 4 was independently studied by the groups of Wang[32] as well as Wang, Hu and Shen[33] via a radical process (Scheme 3.6-20). In the first case, the difluoromethylthiolation of (hetero)aromatic aldehydes was conducted in the presence of TBHP as the radical initiator.

The transformation was not restricted to aromatic aldehydes as aliphatic ones and even ,- unsaturated aldehydes were successfully difluoromethylthiolated. A complementary approach was depicted by Wang, Hu and Shen. In the presence of 4, the combination of NaN

and PIFA permitted the functionalization of a panel of (hetero)aromatic and aliphatic aldehydes in ethyl acetate as a green solvent.

Scheme 3.6-20 Difluoromethylthiolation of aldehydes by means of 4.

In 2018, in the course of their study regarding the trifluoromethylthiosulfonylation of alkynes

via a process merging visible light photocatalysis and gold catalysis, the group of Xu also

investigated the difluoromethylthiosulfonylation reaction of terminal alkynes, leading to the

corresponding trisubstituted alkenes as E isomers (Scheme 3.6-21) [34]. Various functional

groups were tolerated such as ester, halogens, free phenol and the reaction was not restricted

to (hetero)aromatic alkynes as one example of an aliphatic one was depicted. Besides, in the

case of 1-methoxy-4-(1-propyn-1-yl)-benzene as an internal alkyne, the expected product was

obtained in 77% yield as a E/Z mixture of 3:1 (Scheme 3.6-21).

Scheme 3.6-21 Difluoromethylthiosulfonylation of alkynes.

A methodology allowing the synthesis of aliphatic ketones substituted by a SCF

H group at a remote position was developed by Hu, Shen and co-workers [35]. In the presence of AgNO

, SDS as a surfactant (sodium dodecyl sulfate) and K

S

O

, a silver-catalyzed difluoromethylthiolation reaction of a variety of cycloalkanols as precursors of the functionalized alkyl ketones was carried out, offering an access to the corresponding difluoromethylthioethers. Various cycloalkanols were compatible such as cyclobutanols, cyclopropanols, cyclopentanols, cyclohexanols and cycloheptanol (Scheme 3.6-22).

Scheme 3.6-22 Synthesis of aliphatic ketones substituted by a SCF

H group at a remote position.

3.6.3 The SCH

F Motif

As part of the sulfur-containing fluorinated groups, the SCH

F one is underexplored compared to the SCF

H and the SCF

residues. Indeed, prior the twenty first century only a handful of methods were available to access this class of compounds, which could suffer from a lack of stability in some cases. One should mention, the different variants of the fluoro-Pummerer rearrangement, which allowed the conversion of sulfoxides into -fluoromethyl thioethers [36]. Fuchigami and co-workers extensively studied the anodic oxidation of thioethers into the corresponding -fluoromethyl thioethers, although it was restricted to few specific substrates [37]. Finally, the use of electrophilic fluorine source to promote the oxidation of thioethers into -fluoromethyl thioethers was also reported using N-fluoropyridinium salt[38] or F-TEDA- BF

[39].

From 2000, more convenient and general methods were described and are highlighted in this section.

In 2007, Hu and co-workers described the use of chlorofluoromethane as an electrophilic

source of the fluoromethyl moiety [40]. Under basic conditions in DMF, aryl, heteroaryl and

benzyl thiols were readily converted into the corresponding SCH

F-containing derivatives in

good to excellent yields (Scheme 3.6-23).

Scheme 3.6-23 Monofluoromethylation of thiols.

In 2008, Prakash, Olah and co-workers described the synthesis of the sulfonium salt 5, as an electrophilic source of CH

F [41]. Although a single example was described, the reaction of this salt with thiophenol yielded the corresponding and poorly stable -fluoromethylthioether in 88% NMR yield (Scheme 3.6-24).

Scheme 3.6-24 Electrophilic monofluoromethylation of thiophenol using 5.

Complementary to these methods, the group of Hu reported the use of the sulfoximine 6 as a CH

F source [42]. The reaction of 6 with thiols, proceeding presumably according to a S

1 mechanism, provided a straightforward access to the corresponding SCH

F-containing molecules in good yields. The reaction was applied to aryl, heteroaryl and benzyl thiol derivatives (Scheme 3.6-25).

Scheme 3.6-25 Monofluoromethylation of thiols using sulfoximine 6.

In 2017, the group of Shen described the synthesis of a new reagent to introduce the SCH

F

moiety: the S-(fluoromethyl)benzensulfonothioate 7 [43]. This bench-stable reagent 7, easily

prepared from sodium benzenesulfonothioate, was used to convert boronic acids into the

desired aryl-SCH

F-containing molecules in good to excellent yields with an outstanding

functional group tolerance. In the same report, the authors described the radical addition of

the reagent 7 onto terminal alkenes according to an ATRA reaction. The reaction proceeded

nicely with a complete and predictable control of the selectivity of the addition. The products

were obtained in good yields and the functional group tolerance of the process was excellent

(Scheme 3.6-26).

Scheme 3.6-26 Monofluoromethylthiolation of aryl boronic acid and alkenes using 7.

In 2018, Wang[44] and Shen [ 33 ], concomitantly reported the use of the above-mentioned reagent 7 to get access to monofluoromethylthioesters, starting from aldehydes. While Wang was using AMBN (2,2′-Azobis(2-methylbutyronitrile)) to promote the acyl radical formation followed by its recombination with SCH

F moiety onto a broad range of aldehydes, Shen used the combination of NaN

and PIFA to carry out the same transformation. In both cases, yields were moderate to excellent and the reaction proved to be functional group tolerant (Scheme 3.6-27).

Scheme 3.6-27 Synthesis of monofluoromethylthioesters using 7.

Finally, in 2018 the group of Yi described the synthesis of the Bunte salt FCH

SSO

Na 8 for the installation of the SCH

F residue (Scheme 3.6-28). This motif was introduced onto anilines through the in situ formation of the corresponding diazonium salts [45]. This transformation demonstrated an excellent scope, various functionalities were tolerated and heteroaromatic derivatives were compatible. The products were isolated in good to excellent yields. Note that

62%

and 29 examples, 42-91%

a) Wang et al.

7 (0.67 equiv), AMBN (2 equiv) DCE, reflux

b) Shen et al.

76%

and 5 examples, 44-87%

H O

SCH₂F O

H O

S

SCH₂F O

S 7 (1.5 equiv), NaN₃ (2 equiv)

PIFA (2 equiv), EtOAc, rt

the reaction was extended to the functionalization of thiophenol derivatives and the corresponding unsymmetrical disulfides were isolated in good to excellent yields.

Scheme 3.6-28 Monofluoromethylthiolation of anilines and thiols using Bunte salt 8.

3.6.4 The SCF

PO(OEt)

Motif

As another interesting motif that allowed modifications of the physicochemical properties of a molecule, the SCF

PO(OEt)

group was underexplored till 2016. Indeed, most of the previous methodologies were restricted to very few examples and/or focused on the synthesis of reagents to introduce the CF

PO(OEt)

group [46], a phosphate bioisoster [47]. Thus, after 2016, new methods for its introduction or construction have been developed to broaden the scope of available SCF

PO(OEt)

-containing molecules.

In 2016, Besset and co-workers described the synthesis of the reagent 9, an electrophilic source of the SCF

PO(OEt)

group, from a simple aniline derivative and TMSCF

PO(OEt)

in 2 steps (Scheme 3.6-29) [48]. This reagent 9 allowed the introduction of this sulfur-containing fluorinated group on various scaffolds. Indeed, 9 was reacted with indoles or electron rich aromatic derivatives in a SEAr type transformation to form the C-SCF

PO(OEt)

bond. In addition, this reagent was efficient for the introduction of this group onto anilines and thiols.

Finally, the authors demonstrated the possibility to build up a C-SCF

PO(OEt)

when 9 was

reacted with ketones and a -ketoester.

Scheme 3.6-29 Introduction of the SCF

PO(OEt)

motif using the electrophilic reagent 9.

Later in 2019, the same group reported the use of this reagent 9 for the BiCl

-mediated

difunctionalization of alkynes and alkenes, as well as for the synthesis of SCF

PO(OEt)

-

containing alkynes (Scheme 3.6-30) [49]. These transformations afforded the first access to

aliphatic and vinylic SCF

PO(OEt)

-containing molecules and SCF

PO(OEt)

-containing alkynes.

Scheme 3.6-30 Addition of the SCF

PO(OEt)

motif onto alkynes and alkenes using 9.

Another complementary strategy to access the SCF

PO(OEt)

containing molecules relied on the construction of this motif.

In 2016, Poisson and co-workers described the reaction of -diazocarbonyl derivatives with the CuCF

PO(OEt)

reagent prepared from CuSCN and TMSCF

PO(OEt)

(Scheme 3.6-31) [50].

This process allowed the formation of the corresponding -SCF

PO(OEt)

arylacetates in moderate to good yields. The reaction was also extended to the -phenyl diazoketone and - alkyl diazoacetates, albeit with low yields in the last case.

Scheme 3.6-31 Synthesis of -SCF

PO(OEt)

esters and ketone from -diazocarbonyl derivatives.

In 2017, the same authors described the access to -SCF

PO(OEt)

ketones starting from -

bromoketones (Scheme 3.6-32) [51]. Although restricted to secondary -bromoketones, the

corresponding products were obtained in good yields and the functional group tolerance was

good.

Scheme 3.6-32 Reaction of  -bromoketones with TMSCF

PO(OEt)

and CuSCN to access  - SCF

PO(OEt)

ketones.

The same year, these authors reported the construction of arenes substituted with a SCF

PO(OEt)

moiety starting from bis-aryldisulfides (Scheme 3.6-33) [52]. The reaction with the in situ generated CuCF

PO(OEt)

reagent gave an access to the targeted molecules in moderate to good yields.

Scheme 3.6-33 Reaction of disulfides with the in situ generated CuCF

PO(OEt)

.

Finally, in 2019 Goossen and Ou reported the one-pot two-step synthesis of aryl-SCF

PO(OEt)

derivatives starting from aryl diazonium salts (Scheme 3.6-34) [53]. The in situ generation of the aryl thiocyanate followed in a second step by the introduction of the CF

PO(OEt)

motif on the latter, according to a Langlois type substitution, yielded the corresponding aryl- SCF

PO(OEt)

derivatives in moderate to good yields.

Scheme 3.6-34 Synthesis of SCF

PO(OEt)

-containing arenes from diazonium salts.

3.6.5 The SCF

CO

R group (R = Ar, OR)

The adjunction of a ,-difluoromethylcarbonyl motif to the sulfur atom offers new

fluorinated motifs of particular interest. In addition to offer specific physicochemical

properties, it allows easy and various transformations into others functional groups (ketones,

alcohols…). Initially, this motifs was usually build up through classical S

1 reactions [54],

electro- or chemical oxidation[55] and halex process [56]. From 2016, original and milder reaction manifolds were developed to construct or install this motif onto molecules.

Noël and co-workers reported a photocatalyzed addition of the CF

CO

Et radical on a cysteine derivative (Scheme 3.6-35) [57]. The developed process was applied in batch and in continuous flow conditions. The targeted compound was obtained in good yield in batch (75%) and 81% yield under continuous flow conditions (residence time = 5 min). Note that the methodology was extended to the construction of SRf residues (7 examples).

Scheme 3.6-35 Synthesis of SCF

CO

Et cysteine analog.

In 2017, Shen and co-workers reported the first electrophilic reagent to introduce the

SCF

CO

Et motif: the [[(ethoxycarbonyl)difluoromethyl]thio]phthalimide 10 (Scheme 3.6-36)

[58]. This reagent, conveniently prepared from phtalimide and BrCF

CO

Et or TMSCF

CO

Et in

a three-step sequence, was reacted with various nucleophiles. Reagent 10 was reacted with

indoles, pyrroles, thiophene and electron rich arenes according to a SEAr pathway to build up

SCF

CO

Et-containing arenes and heteroarenes. In addition, this reagent proved to be reactive

with thiol nucleophiles, giving an access to non-symmetrical disulfides. Finally, the formation

of the C-SCF

CO

Et bond was possible starting from -ketoesters, 3-aryloxindoles or 3-

arylbenzofuranones.

Scheme 3.6-36 Introduction of the SCF

CO

Et group onto electron rich arenes, heteroarenes, thiols,

-ketoesters, oxindoles and benzofuranones using the electrophilic reagent 10.

In the same vein, Billard and co-workers reported the synthesis and the application of the (methoxycarbonyl)difluoromethanesulfonamide 11 as a practical reagent to introduce the SCF

CO

Me motif (Scheme 3.6-37) [59]. Similarly to the reagent 10, developed by Shen, this reagent was reacted with electron rich arenes and heteroarenes giving the corresponding

N O

O

1. S₂Cl₂, Et₃N 2. Cl₂/CHCl₃ or SO₂Cl₂ 3. TMSCF₂CO₂Et, AgF

N O

O

SCF₂CO₂Et Preparation of reagent 10:

Pathway A:

Pathway B:

ClSCF₂CO₂Et prepared in 2 steps

from BrCF₂CO₂Et N

O

O H

K N

O

O

SCF₂CO₂Et

10 10

a) Reaction with electron rich arenes and heteroarenes:

N H O₂N

SCF₂CO₂Et N

H O₂N

10 (1.2 equiv), MgBr₂ (1.5 equiv) DCE, 80 °C

86%

and 14 examples, 56-91%

c) Reaction with b-ketoesters, oxindoles and benzofuranones:

SH S

SCF2CO2Et 91%

and 5 examples, 74-85%

b) Reaction with thiols:

10 (1.2 equiv), K₂CO₃ (1.5 equiv) CH₂Cl₂, rt

89%

and 5 examples, 72-95%

MeO MeO

10 (1.2 equiv), MgBr₂ (1 equiv) Toluene, 80 °C

10 (1.2 equiv), K₂CO₃ (1.5 equiv) CH₂Cl₂, rt

72%

and 3 examples, 88-92%

N F Boc

Ph SCF₂CO₂Et O N

F Boc O Ph

10 (1.2 equiv), K₂CO₃ (1.5 equiv) CH₂Cl₂, rt

Ar = 4-Cl-C₆H₄, 91%

Ar = 3,4-OCH2O-C6H3, 91%

O

Ar SCF₂CO₂Et O O

O Ar

O

CO₂Me SCF₂CO₂Et Br

O Br

CO₂Me

products in high yields. Complementary, this reagent allowed the -functionalization of ketones, as well as cyclization reactions to access polysubstituted benzofuran, benzothiophene and isochromenone bearing the SCF

CO

Me motif, starting from the appropriate alkyne.

Scheme 3.6-37 Synthesis of SCF

CO

Et-containing electron rich (hetero)arenes and ketones.

Later, Zheng and Zhao described the construction of the SCF

CO

Et motifs starting from alkyl

bromides, -bromoketones and aryl diazonium salts (Scheme 3.6-38) [60]. This reaction

proceeded through the initial formation of the thiocyanate derivatives, followed by a Langlois

type substitution using TMSCF

CO

Et and CsF as an activator, a concept already described by

Goossen [61]. Regarding the reaction with alkyl halides, the reaction proceeded well with

benzyl bromides and various alkyl bromides along with a good functional group tolerance. -

Bromo ketones gave the -SCF

CO

Et ketones in low to moderate yields, while aryl diazonium

salts gave the aryl-SCF

CO

Et derivatives in moderate to excellent yields.

Scheme 3.6-38 Construction of the SCF

CO

Et motif on alkyl bromides, benzyl bromides and aryl diazonium salts.

Finally, in 2019, Koenigs and Jana described an elegant Doyle-Kirmse rearrangement using the reagent 12 to access quaternary center bearing the SCF

CO

Et motif (Scheme 3.6-39) [62].

Although, the reaction was restricted to -aryl diazoacetates, the reaction of 12 in the presence of Rh

(OAc)

furnished the desired compounds in good to excellent yields and a large panel of -aryl diazoacetates was successfully reacted. In addition, the authors demonstrated the possible formation of the product under metal free conditions, using blue light to promote the formation of the carbene involved in the Doyle-Kirmse rearrangement.

Scheme 3.6-39 Doyle-Kirmse rearrangement toward the formation of quaternary carbon centers bearing the SCF

CO

Et motif.

3.6.6 The SCF

Rf Motif

Since the pioneer work from Goossen, who used Me

NSC

F

as a SRf source[63] and the design

by the group of Billard of an electrophilic source (ArNMeSRf) [64], few reports dealt with the

direct introduction of SRf residue. In 2016, using the combination of RfSO

Cl with (EtO)

POH,

the group of Yi reported few examples of the direct introduction of SC

F

and SC

F

residues

on indoles derivatives (4 examples) as part of a more general study regarding the

fluoroalkylthiolation with fluoroalkylsulfonyl chlorides (Scheme 3.6- 40) [ 23 ].

Scheme 3.6-40 Perfluoroalkylthiolation of electron rich arenes with an electrophilic source in situ generated from RfSO

Na

One year later, in the course of their study to generate in situ an electrophilic SCF

H source from HCF

SO

Na with (EtO)

POH and TMSCl, Yi, Zhang and co-workers extended their methodology to the introduction of other SRf groups (SRf = SC

F

and SC

F

) on 1,3,5- trimethoxybenzene (2 examples, Scheme 3.6- 41) [ 25 ].

Scheme 3.6-41 Perfluoroalkylthiolation of 1,3,5-trimethoxybenzene with an electrophilic source in situ generated from RfSO

Na

In 2017, the group of Yi developed a methodology to build up a S-Rf bond using the corresponding RfSO

Na as they depicted a silver catalyzed perfluoroalkylation of thiols [ 10 ].

With this approach, a panel of (hetero)aromatic and aliphatic thiols was functionalized. The reaction turned out to be tolerant to several functional groups such as carboxylic acids, free alcohol and halogens (Scheme 3.6-42).

Scheme 3.6-42 Perfluoroalkylthiolation of thiol derivatives with RfSO

Na.

3.6.7 Conclusions and Perspectives

The last decade, tremendous advances have been witnessed regarding the development of new sulfur-

containing fluorinated groups. Indeed, complementary to the SCF

motif, the SCF

H and more recently

the SCH

F, SCF

CO

Et, SCF

PO(OEt)

, SRf have been implemented to the medicinal chemist toolbox. In

this chapter, we summarized the recent progress made in that field. In addition to these pioneer works,

we believe that important milestones to introduce or build up these motifs as well as newly designed

sulfur-containing fluorinated motifs will appear in the forthcoming years.

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